Programmed cell death plays a central role in development and in multiple diseases, notably cancer and neurodegenerative disorders. -The long-term objective of this proposed research is to further understand the mechanisms of programmed cell death and its role in development. The model being used is the ovary of the fruitfly, Drosophila melanogaster, a system with unique advantages for the study of cell death. Programmed cell death of ovarian nurse cells is essential for proper oocyte development. Nurse cells possess distinct traits which make them an ideal model for analyzing cell death in vivo. These cells are abundant, die synchronously in clusters, and are large, making them amenable to subcellular analyses. Furthermore, disruption of nurse cell death results in sterility, a phenotype that permits straightforward genetic analysis. This proposal addresses multiple aspects of the nurse cell death pathway. The specific aims are to 1) further address the requirement for caspases in this pathway by the expression of constitutively active Drosophila caspase- 1 (Dcp- 1) in the germline, the characterization of new alleles of dcp-1, and the characterization of the caspase Drice; 2) isolate additional genes involved in nurse cell death by histological examination of mutants previously shown to have defects in oogenesis; and 3) test the role of individual caspase targets during cell death in vivo by the expression of cleavage-defective molecules. These experiments should yield an understanding of the molecules that are critical for nurse cell death, from the initial signal to the final proteolyzed targets. This knowledge is likely to have implications for other cell death pathways in Drosophila and other organisms.